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Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction.

Lichtenauer M, Mildner M, Baumgartner A, Hasun M, Werba G, Beer L, Altmann P, Roth G, Gyöngyösi M, Podesser BK, Ankersmit HJ - Basic Res. Cardiol. (2011)

Bottom Line: A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells.Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue.The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University Vienna, Währinger Gürtel 18-20, Vienna, Austria.

ABSTRACT
Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

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Results 3 days after AMI induction: H&E stained rat myocardium 3 days after LAD ligation. The cellular infiltrate appears to be more consolidated in apoptotic PBMC treated animals (a–d). The total area of necrosis was significantly reduced in both treatment groups compared to controls (e). Below, myocardial tissue stained for CD68 is shown (f–i). Quantification of positively stained cells per high power-field (HPF) indicated higher numbers of macrophages in both treatment groups (h–j). When tissue specimens were stained for c-kit (k–n), more of these cell populations could be detected in the epicardial zone in rats injected with apoptotic cells (m–o). Concomitantly, more cells staining positive for FLK-1/VEGF receptor 2 were found in the same areas (p–t)
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Fig1: Results 3 days after AMI induction: H&E stained rat myocardium 3 days after LAD ligation. The cellular infiltrate appears to be more consolidated in apoptotic PBMC treated animals (a–d). The total area of necrosis was significantly reduced in both treatment groups compared to controls (e). Below, myocardial tissue stained for CD68 is shown (f–i). Quantification of positively stained cells per high power-field (HPF) indicated higher numbers of macrophages in both treatment groups (h–j). When tissue specimens were stained for c-kit (k–n), more of these cell populations could be detected in the epicardial zone in rats injected with apoptotic cells (m–o). Concomitantly, more cells staining positive for FLK-1/VEGF receptor 2 were found in the same areas (p–t)

Mentions: Since the inflammatory response after acute ischaemia determines the road map to ventricular dilation, we performed histological analysis after 72 h after AMI in order to study short term effects of intravenous (IV) or intramyocardial (IM) injection of apoptotic cell suspensions. H&E stained specimens obtained from control AMI animals evidenced a mixed cellular infiltrate in the wound areas in accordance with granulation tissue with abundance of neutrophils, macrophages/monocytes, lymphomononuclear cells admixed to dystrophic cardiomyocytes within the first 72 h after AMI (Fig. 1a,b). In contrast, rats treated with apoptotic PBMC suspensions evidenced a dense monomorphic infiltrate in wound areas (Fig. 1c,d). Furthermore, the total area of necrosis was significantly smaller in rats injected with apoptotic cells in comparison to controls (Fig. 1e). Immunohistological analysis revealed that the cellular infiltrate in both treatment groups (intravenous and intramyocardial injection) was composed of abundant CD68+ monocytes/macrophages that was much weaker in the control group (Fig. 1f–j). Cell counts quantified per high power-field (HPF) were 28.6 ± 2.4 (±SEM) in control, 36.0 ± 3.5 (±SEM) in animals injected with non-irradiated viable cells compared to 55.3 ± 3.4 and 76.5 ± 5.9 (± SEM) in rats treated with apoptotic cells (IV or IM, respectively). In addition, most of the medium-sized monocytoid cells were identified to be highly positive for c-kit (CD117) and vascular endothelial growth factor receptor 2 (FLK-1). High power-field (HPF) cell counts for c-kit were 68.0 ± 3.1(±SEM) in controls, 77.0 ± 4.6 (±SEM) in the group injected with viable cell versus 121.2 ± 9.4 (±SEM) in IV and 168.6 ± 12.4 (±SEM) in IM injected rats (Fig. 1k–o). For FLK-1, values were 58.3 ± 5.6 (±SEM) in controls, 86.0 ± 7.0 (±SEM) for viable cell injected rats, 170.3 ± 7.1 (±SEM) for IV and 202.0 ± 9.4 (±SEM) for IM injected rats (Fig. 1p–t). Expression of these three cellular markers was more accentuated in rats injected with apoptotic cell suspensions compared to the control AMI group. (see representative images Fig. 1, n = 5–6 per group).Fig. 1


Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction.

Lichtenauer M, Mildner M, Baumgartner A, Hasun M, Werba G, Beer L, Altmann P, Roth G, Gyöngyösi M, Podesser BK, Ankersmit HJ - Basic Res. Cardiol. (2011)

Results 3 days after AMI induction: H&E stained rat myocardium 3 days after LAD ligation. The cellular infiltrate appears to be more consolidated in apoptotic PBMC treated animals (a–d). The total area of necrosis was significantly reduced in both treatment groups compared to controls (e). Below, myocardial tissue stained for CD68 is shown (f–i). Quantification of positively stained cells per high power-field (HPF) indicated higher numbers of macrophages in both treatment groups (h–j). When tissue specimens were stained for c-kit (k–n), more of these cell populations could be detected in the epicardial zone in rats injected with apoptotic cells (m–o). Concomitantly, more cells staining positive for FLK-1/VEGF receptor 2 were found in the same areas (p–t)
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Related In: Results  -  Collection

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Fig1: Results 3 days after AMI induction: H&E stained rat myocardium 3 days after LAD ligation. The cellular infiltrate appears to be more consolidated in apoptotic PBMC treated animals (a–d). The total area of necrosis was significantly reduced in both treatment groups compared to controls (e). Below, myocardial tissue stained for CD68 is shown (f–i). Quantification of positively stained cells per high power-field (HPF) indicated higher numbers of macrophages in both treatment groups (h–j). When tissue specimens were stained for c-kit (k–n), more of these cell populations could be detected in the epicardial zone in rats injected with apoptotic cells (m–o). Concomitantly, more cells staining positive for FLK-1/VEGF receptor 2 were found in the same areas (p–t)
Mentions: Since the inflammatory response after acute ischaemia determines the road map to ventricular dilation, we performed histological analysis after 72 h after AMI in order to study short term effects of intravenous (IV) or intramyocardial (IM) injection of apoptotic cell suspensions. H&E stained specimens obtained from control AMI animals evidenced a mixed cellular infiltrate in the wound areas in accordance with granulation tissue with abundance of neutrophils, macrophages/monocytes, lymphomononuclear cells admixed to dystrophic cardiomyocytes within the first 72 h after AMI (Fig. 1a,b). In contrast, rats treated with apoptotic PBMC suspensions evidenced a dense monomorphic infiltrate in wound areas (Fig. 1c,d). Furthermore, the total area of necrosis was significantly smaller in rats injected with apoptotic cells in comparison to controls (Fig. 1e). Immunohistological analysis revealed that the cellular infiltrate in both treatment groups (intravenous and intramyocardial injection) was composed of abundant CD68+ monocytes/macrophages that was much weaker in the control group (Fig. 1f–j). Cell counts quantified per high power-field (HPF) were 28.6 ± 2.4 (±SEM) in control, 36.0 ± 3.5 (±SEM) in animals injected with non-irradiated viable cells compared to 55.3 ± 3.4 and 76.5 ± 5.9 (± SEM) in rats treated with apoptotic cells (IV or IM, respectively). In addition, most of the medium-sized monocytoid cells were identified to be highly positive for c-kit (CD117) and vascular endothelial growth factor receptor 2 (FLK-1). High power-field (HPF) cell counts for c-kit were 68.0 ± 3.1(±SEM) in controls, 77.0 ± 4.6 (±SEM) in the group injected with viable cell versus 121.2 ± 9.4 (±SEM) in IV and 168.6 ± 12.4 (±SEM) in IM injected rats (Fig. 1k–o). For FLK-1, values were 58.3 ± 5.6 (±SEM) in controls, 86.0 ± 7.0 (±SEM) for viable cell injected rats, 170.3 ± 7.1 (±SEM) for IV and 202.0 ± 9.4 (±SEM) for IM injected rats (Fig. 1p–t). Expression of these three cellular markers was more accentuated in rats injected with apoptotic cell suspensions compared to the control AMI group. (see representative images Fig. 1, n = 5–6 per group).Fig. 1

Bottom Line: A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells.Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue.The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University Vienna, Währinger Gürtel 18-20, Vienna, Austria.

ABSTRACT
Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

Show MeSH
Related in: MedlinePlus